AU3442201A - Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid - Google Patents
Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid Download PDFInfo
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- AU3442201A AU3442201A AU34422/01A AU3442201A AU3442201A AU 3442201 A AU3442201 A AU 3442201A AU 34422/01 A AU34422/01 A AU 34422/01A AU 3442201 A AU3442201 A AU 3442201A AU 3442201 A AU3442201 A AU 3442201A
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- pharmaceutical composition
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- monothioglycerol
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- thioglycolic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
WO 01/56575 PCT/USO1/00648 PHARMACEUTICAL COMPOSITION COMPRISING PEMETREXED TOGETHER WITH MONOTHIOGLYCEROL L-CYSTEIN OR THIOGLYCOLIC ACID The present invention relates to a liquid composition comprising the known 5 compound pemetrexed, in particular, the present invention relates to a liquid composition comprising pemetrexed and an antioxidant; which liquid composition is stable and pharmaceutically elegant. Certain folic acid antimetabolites are known to be antineoplastic agents. These compounds inhibit enzymatic conversion involving metabolic derivatives of 10 folic acid. One such compound, described by United States Patent 5,344,932, is currently being developed for potential use as a pharmaceutical agent. This compound, known as "pemetrexed", is most desirably formulated into a concentrated liquid for administration as an infusion dosage form. Pemetrexed Disodium is the active ingredient in the anticancer drug ALIMTA now in clinical development by Eli 15 Lilly and Company. The formulation teachings of the US Patent 5,344,932 provide that the compounds claimed therein can be administered parenterally. A ready to use, stable, ready to reconstitute solution that could be stored at room temperature is particularly desired for a pharmaceutical such as pemetrexed, 20 wherein such ready to use formulation provides easier, safer handling, storage, and distribution. It is particularly desirable if the stable formulation can be prepared without the use of freeze drying techniques. The desired liquid formulation can offer enhanced safety for caregiver handling of the cytotoxic materials. Further, a stable, ready to use formulation is more acceptable to the customer. 25 It was discovered that a simple, isotonic saline solution of pemetrexed is not pharmaceutically acceptable for commercial purposes due to degradation of the solution to form unacceptable related substances. It has now been discovered that pharmaceutically acceptable, concentrated, ready to use, liquid solutions of pemetrexed may be prepared when the formulation includes certain antioxidants, 30 including monothioglycerol, L-cysteine, and thioglycolic acid. Other antioxidants WO 01/56575 PCT/USO1/00648 -2 were studied; however, surprisingly, of the antioxidants studied, only these provided the desired formulation characteristics described herein. The claimed formulation exhibits acceptable stability, retains a pharmaceutically desirable appearance, maintains the desired enatiomeric stability, 5 and fulfils the health care provider's desire for a stable, ready to use liquid formulation. Additionally, the formulation provided herein, is suitable for parenteral dosage, can be delivered to the health care provider in a clear vial and can be stored at temperatures above 4 (four) Celcius in a highly concentrated state. The present invention addresses the need for a pharmaceutically stable liquid 10 pemetrexed formulation having both color stability and acceptable shelf life stability with regard to retaining the solution dosage form and avoiding unacceptable degradation to undesired related substances. Additionally, the claimed formulations can be diluted to the desired administration concentration by the health care provider. Finally, the formulations provided herein do not require the addition of any 15 preservative, other than the antioxidant, in order to retain the desired concentration and stability. The present invention particularly provides a pharmaceutical composition comprising: a) pemetrexed; 20 b) at least one antioxidant selected from the group consisting of i) monothioglycerol, ii) L-cysteine, iii) thioglycolic acid; and c) a pharmaceutically acceptable excipient. 25 The three antioxidants are uniquely effective for the claimed formulation. Surprisingly, common antioxidants, such as sodium metabisulfite, ascorbic acid, sodium EDTA, monoethanolamine gentisate, sodium formaldehyde sulfoxylate, sodium bisulfite, did not provide the desired formulation characteristics. 30 An especially preferred antioxidant is monothioglycerol.
WO 01/56575 PCT/USO1/00648 -3 The concentration of monothioglycerol is most preferably from about 1 part per million to 8.0 mg/ml, which concentration may be optimized for a given formulation based on the oxygen concentration contacting the formulation. The concentration of monothioglycerol may preferably be at least 0.6 mg/ml, more 5 preferably at least 0.8 mg/ml, especially preferably is at least 1.0 mg/ml. The concentration of monothioglycerol is preferably up to 6 mg/ml, more preferably up to 5 mg/ml, and most preferably is up to 3 mg/ml. It may be preferred that the concentration of monothioglycerol is from about 0.6 mg/ml to about 6 mg/ml. More preferably, the concentration of monothioglycerol 10 is from about 0.8 mg/ml to about 5.0 mg/ml. It is especially preferred that the concentration of monothioglycerol is at least 1.0 mg./ml. An especially desired concentration is from 1.40 mg/ml to about 3.0 mg/ml. A further desired concentration is from about 2 mg/ml to about 3 mg/ml. A further preferred concentration of monothioglycerol is from about 1.2 mg/ml to about 2.4 mg/ml. 15 In general, the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is most preferably from about 1 part per million to 8.0 mg/ml, which concentration may be optimized for a given formulation based on the oxygen concentration contacting the formulation. L-cysteine or thioglycolic acid are often most effective at a higher pH. It may be preferred that the concentration of 20 monothioglycerol, L-cysteine or Thioglycolic acid is from about 1.0 mg/ml to about 6 mg/ml. More preferably, the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is from about 0.8 mg/ml to about 5.0 mg/ml. It is especially preferred that the concentration of monothioglycerol, L-cysteine or Thioglycolic acid is at least 1.0 mg./mil. An especially desired concentration for monothioglycerol, L 25 cysteine or Thioglycolic acid is from 1.40 mg/ml to about 3.0 mg/ml. A further desired concentration is from about 2 mg/ml to about 3 mg/ml. A further preferred concentration of monothioglycerol, L-cysteine or Thioglycolic acid is from about 1.2 mg/ml to about 2.4 mg/ml. It is preferred to have a concentration of from about 0.1 (one tenth) mg/mi to 7 mg/ml. When the antioxidant is monothioglycerol or L 30 cycsteine, the preferred concentration range is from about 0.1 (one tenth)mg/ml to about 10.0 mg/ml.
WO 01/56575 PCT/USO1/00648 -4 The concentration of L-cysteine is preferably greater than 0.1 (one tenth) mg/ml, more preferably greater than 0.5 (one half) mg/ml and most preferably greater than 1 (one) mg/ml. The concentration of L-cysteine is preferably less than 10 (ten) mg/ml, more 5 preferably less than 8 (eight) mg/ml, and most preferably less than 6 (six) mg/ml. The concentration of thioglycolic acid is preferably greater than 0.1 (one tenth) mg/ml, more preferably greater than 0.5 (one-half) mg/ml and most preferably greater than 1 (one) mg/ml. The concentration of thioglycolic acid is preferably less than 10 (ten) mg/ml, 10 more preferably less than 8 (eight) mg/ml, and most preferably less than 6 (six) mg/ml. Additionally, combinations of the three antioxidants, selected from monothioglycerol, L-cysteine and thioglycerol, may also be used in this invention. The concentration of pemetrexed is preferably from about 20 to about 100 15 mg/ml. It is especially preferred that the pemetrexed concentration is from about 30 mg/ml to about 70 mg/ml. A further preferred embodiment is when the pemetrexed concentration is from about 35 mg/mI to about 50 mg/ml. A further preferred embodiment is a pemetrexed concentration of from 38 mg/mI to about 44 mg/ml. An especially desired concentration of pemetrexed is about 40 mg/ml. 20 As used herein, the term "pemetrexed" refers to the stable salts, acids and free base forms thereof. The term includes, for example, the free acid, the pharmaceutically acceptable alkali metal, alkaline earth metal, non-toxic metal, ammonium, and substituted ammonium salts, such as for example, the sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, 25 trimethylammonium, triethylammonium, monoethanolammonium, triethanolammonium, pyridinium, substituted pyridinium, and the like. The substituted ammonium salts are one especially preferred group of salts. As used herein, the term "pharmaceutically acceptable excipient" means a pharmaceutically acceptable formulation carrier, solution or additive to enhance the 30 formulation characteristics. Such additives are well known to the skilled artisan. While any pharmaceutically acceptable diluent is suitable, an especially preferred WO 01/56575 PCT/USO1/00648 -5 excipient for parenteral administration is saline solution. For example, sodium chloride, mannitol and the like. The disodium salt of pemetrexed is particularly preferred for use in the present formulation. 5 The pH of the formulation is most preferably from about 5.5 to about 12. The formulation is more preferably from about pH 7 to about 11. It is especially desired that the pH of the formulation is from 8.0 to 9.0. It is further preferred that the pH is from about 8 to about 9 when the antioxidant is monothioglycerol. When the antioxidant is L-cysteine or thioglycolic acid or any salt form thereof, then the 10 preferred pH is about 8 to about 10. The artisan will appreciate that combinations of these antioxidants can provide new preferred pH ranges. Standard modifications of the composition can provide compositions of various pH within the contemplation of this invention. It is generally preferred that the process for preparing the formulation includes 15 the use of a purge of an inert gas. Such inert gases are for example, nitrogen, argon, and the like. The use of an isolator to maintain low oxygen conditions is desirable, but not required for storage of the present formulation. While any pharmaceutically acceptable stopper may be used to seal the vial containing the formulation, it is preferred to seal the vial with a stopper which is 20 siliconized. A sterlized teflon coated stopper is desired for sealing the storage vial. Most pharmaceutically acceptable liquid formulation vials or containers can be used to dispense the claimed formulation. It is desired that the containing vessel minimizes the concentration of oxygen that reaches the formulation. Thus, vials or ampules are especially desired vessels for the claimed formulation. A sealed vial is 25 especially desired for commercial purposes in most countries. The artisan will appreciate that the use of depyrogenated prewashed vials is desired for the storage of a sterile liquid formulation that is intended for parenteral use. The vial may be colored; however, a clear vial is acceptable for storage of the formulation. Any pharmaceutically acceptable material may be used to make the 30 formulation container; however, glass is an especially preferred container material. A WO 01/56575 PCT/USO1/00648 -6 glass vial is a preferred container. Other packaging materials for parenterals like plastic vials are preferred options as well. For example, plastic vials may be useful. It may be desirable to protect the bulk solution from light during the process of preparing the formulation; however, such protection is not required for the present 5 formulation. The resulting formulation can be sterlized using methods known to the artisan. Such sterilisation methods may include, for example, sterile filtration or heating. It is especially beneficial that the presently claimed formulation is stable during heat sterilization. 10 It is preferred that the headspace of the vial contains less than about 8% (eight percent) v/v Oxygen; however, the headspace of the vial may contain more than 8% oxygen if other conditions of the formulation are appropriately adjusted. It is more preferred that the headspace of the vial contains from about 2% to about 5% Oxygen. It is especially preferred that the headspace contains from about 3% to about 15 5% Oxygen. It is further preferred that the headspace contains less than about one (1) ppm oxygen. Also, preferred is when the headspace oxygen content is less than about 0.1% (one tenth percent ) v/v oxygen. It is also a preferred condition that the headspace of the vial is less than about 1% (one percent) oxygen. The headspace of the vial can be adjusted to minimize the 20 formulation contact with oxygen. It is generally desired that the headspace is not more than about 1/3 (one third) of the total volume of the container, with the fill taking at least about 2/3 (two thirds) of the total volume of the container. For example, it may be preferred that 5 ml of fill be used for a 7.5 ml vial. If a greater headspace ratio to fill is desired, then the concentration of the antioxidant may be 25 adjusted as necessary. The pharmaceutical formulation provided herein is suitable for both human clinical use and veterinarian use for animals. Pemetrexed can be prepared using the processes described in United States Patent 5,473,071, hereby incorporated by reference in its entirety. Compositions of 30 pemetrexed are useful to treat cancer, as described in the 5,344,932 patent as well as in Seminars in Oncology, Vol. 26, No. 2, Supplement 6 (April 1999).
WO 01/56575 PCT/USO1/00648 -7 Monothioglycerol is commercially available from suppliers of fine chemicals which are well known to the artisan. To further clarify, Monothioglycerol is Chemical Abstracts number: 96-27-5. Likewise, L-cysteine (CAS: 52-90-4), L-cysteine hydrochloride monohydrate 5 (CAS: 7048-04-6), L-cysteine hydrochloride monohydrate anhydrous (CAS: 52-89-1) and thioglycolic acid (CAS:68-11-1) are readily obtained from suppliers of fine chemicals. Description of Preferred Embodiments. The Present invention is seen more fully by the examples given below. 10 Example 1 Pemetrexed, was prepared as a 40 mg/mI solution in water. Monothioglycerol was prepared as a 2.4 mg/mI solution using water for injection. The pH of the monothioglycerol solution was adjusted to 8.5 using sodium hydroxide. 15 The bulk solution was protected from light. The solution was purged with nitrogen for twenty minutes and then sterile filtered. The formulation was dispensed into prewashed, depyrogenated vials and then stoppered with a prewashed, presterilized teflon coated stopper. Caps were attached using a crimper. The sterile filtration and dispensing steps were conducted using a nitrogen isolator (5% v/v 20 Oxygen). The solution filled vials were heat sterilized. Example 2 A pharmaceutical composition was prepared substantially as described herein by Example 1, except that the antioxidant was 0.03% L-Cysteine and the pemetrexed 25 concentration was four percent (4%). Example 3 A pharmaceutical composition was prepared substantially as described herein by Example 1, except that the antioxidant was 0.03% Thioglycolate and the pemetrexed concentration was four percent (4%). 30
Claims (20)
1. A pharmaceutical composition comprising: a) pemetrexed; 5 b) at least one antioxidant selected from the group consisting of: c) monothioglycerol, ii) L-cysteine, and iii) thioglycolic acid; and c) a pharmaceutically acceptable excipient. 10
2. A pharmaceutical composition as claimed by Claim 1 wherein the composition is a liquid formulation suitable for parenteral administration.
3. A pharmaceutical composition as claimed by any one of Claims 1 and 2 wherein 15 pemetrexed is the disodium salt.
4. A pharmaceutical composition as claimed by any one of Claims 1 to 3 wherein the antioxidant is monothioglycerol. 20
5. A pharmaceutical composition as claimed in any one of Claims 1 to 4 wherein the monothioglycerol concentration is from about 1 (one) part per million to about 8 (eight) milligrams per milliliter.
6. A pharmaceutical composition of Claim 5 wherein the monothioglycerol 25 concentration is from about 1 (one) mg/ml to about 6 (six) mg/ml.
7. A pharmaceutical composition of Claim 6 wherein the monothioglycerol concentration is from about 1 (one) mg/ml to about 2.5 (two and one half) mg/ml. 30
8. A pharmaceutical composition of Claim 4 wherein the monothioglycerol concentration is from about 0.5 (one half) mg/ml to about 3 (three) mg/ml. WO 01/56575 PCT/USO1/00648 -9
9. A pharmaceutical composition as claimed by any one of Claims 1 to 3 wherein the antioxidant is L-cysteine. 5
10. A pharmaceutical composition of Claim 9 wherein the L-cysteine concentration is from about 1 (one) part per million to about 8 (eight) mg/mi.
11. A pharmaceutical composition of Claim 10 wherein the L-cysteine concentration is from about 1 (one) mg/mi to about 6 (six) mg/ml. 10
12. A pharmaceutical composition of Claims 1 to 3 wherein the antioxidant is thioglycolic acid. 15
13. A pharmaceutical composition of Claim 12 wherein the thioglycolic acid concentration is from about 1 (one) part per million to about 8 (eight) mg/mi.
14. A pharmaceutical composition of Claim 13 wherein the thioglycolic acid concentration is from about 0.1 (one-tenth) mg/mi to about 6 (six) mg/mi. 20
15. A pharmaceutical composition of Claim 4 wherein the monothioglycerol concentration is from about 0.1 (one tenth) mg/ml to about 10 (ten) mg/ml.
16. A pharmaceutical composition of Claim 15 wherein the monothioglycerol 25 concentration is from about 0.1 (one tenth) mg/mi to about 6 (six) mg/mi.
17. A pharmaceutical composition of Claim 9 wherein the L-cysteine is from about 0.1 (one tenth) mg/mi to about 10 (ten) mg/ml. 30
18. A pharmaceutical composition of Claim 17 wherein the L-cysteine is from about 0.1 (one tenth) mg/mi to about 6 (six) mg/mi. WO 01/56575 PCT/USO1/00648 - 10
19. A pharmaceutical composition of Claim 12 wherein the thioglycolic acid is from about 0.1 (one tenth) mg/ml to about 10 (ten) mg/ml. 5
20. A pharmaceutical composition of Claim 19 wherein the thioglycolic acid is from about 0.1 (one tenth) mg/mi to about 6 (six) mg/ml.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0002691A GB2358799A (en) | 2000-02-04 | 2000-02-04 | A pharmaceutical composition comprising pemetrexed and an antioxidant |
| GB0002691 | 2000-02-04 | ||
| GB0019599A GB2365768A (en) | 2000-08-09 | 2000-08-09 | Stable liquid composition containing pemetrexed |
| GB0019599 | 2000-08-09 | ||
| PCT/US2001/000648 WO2001056575A1 (en) | 2000-02-04 | 2001-01-23 | Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU3442201A true AU3442201A (en) | 2001-08-14 |
Family
ID=26243579
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU34422/01A Abandoned AU3442201A (en) | 2000-02-04 | 2001-01-23 | Pharmaceutical composition comprising pemetrexed together with monothioglycerol l-cystein or thioglycolic acid |
Country Status (31)
| Country | Link |
|---|---|
| EP (1) | EP1265612B1 (en) |
| JP (1) | JP2003521518A (en) |
| KR (1) | KR20020081293A (en) |
| CN (1) | CN1396828A (en) |
| AR (1) | AR027360A1 (en) |
| AT (1) | ATE267601T1 (en) |
| AU (1) | AU3442201A (en) |
| BR (1) | BR0107958A (en) |
| CA (1) | CA2399124A1 (en) |
| CO (1) | CO5280222A1 (en) |
| CZ (1) | CZ20022654A3 (en) |
| DE (1) | DE60103512T2 (en) |
| DK (1) | DK1265612T3 (en) |
| DZ (1) | DZ3269A1 (en) |
| EA (1) | EA004708B1 (en) |
| ES (1) | ES2220716T3 (en) |
| HK (1) | HK1052461A1 (en) |
| HR (1) | HRP20020636A2 (en) |
| HU (1) | HUP0300709A3 (en) |
| IL (1) | IL150475A0 (en) |
| MX (1) | MXPA02007191A (en) |
| MY (1) | MY129450A (en) |
| NO (1) | NO20023379L (en) |
| NZ (1) | NZ519727A (en) |
| PE (1) | PE20011223A1 (en) |
| PL (1) | PL356705A1 (en) |
| PT (1) | PT1265612E (en) |
| SK (1) | SK10982002A3 (en) |
| SV (1) | SV2002000301A (en) |
| TR (1) | TR200401436T4 (en) |
| WO (1) | WO2001056575A1 (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050042280A1 (en) * | 2001-12-28 | 2005-02-24 | Rogers Tracey L. | Aqueous based pharmaceutical formulations of water-soluble prodrugs of propofol |
| KR101069128B1 (en) * | 2011-03-10 | 2011-09-30 | 건일제약 주식회사 | Process for preparing pharmaceutical formulation in form of antioxidant-free solution for injection comprising pemetrexed or its salt |
| KR20130122065A (en) * | 2012-04-30 | 2013-11-07 | 씨제이제일제당 (주) | Stabilized aqueous preparation for injection containing pemetrexed |
| EP2666463A1 (en) | 2012-05-21 | 2013-11-27 | Synthon BV | Stabilized liquid composition comprising pemetrexed |
| DE102012010774A1 (en) | 2012-05-31 | 2013-12-05 | Stada Arzneimittel Ag | Pharmaceutical pemetrexed solution |
| KR101260636B1 (en) | 2012-11-29 | 2013-05-13 | 씨제이제일제당 (주) | A stabilized pemetrexed preparation |
| KR101485243B1 (en) | 2013-05-08 | 2015-01-21 | 씨제이헬스케어 주식회사 | A stabilized pemetrexed preparation |
| JP6094388B2 (en) * | 2013-06-07 | 2017-03-15 | ニプロ株式会社 | Injectable composition comprising pemetrexed |
| CN103340826B (en) * | 2013-07-05 | 2015-09-09 | 浙江震元制药有限公司 | metadoxine composition for injection and preparation method thereof |
| WO2015050230A1 (en) | 2013-10-03 | 2015-04-09 | 富士フイルム株式会社 | Injection preparation and method for producing same |
| KR101703980B1 (en) | 2013-12-30 | 2017-02-08 | 주식회사 삼양바이오팜 | Antioxidant-free pharmaceutical composition and preparation method thereof |
| JP6099810B2 (en) * | 2014-03-28 | 2017-03-22 | 富士フイルム株式会社 | Injection solution preparation and method for producing the same |
| WO2016024369A1 (en) * | 2014-08-13 | 2016-02-18 | テバ製薬株式会社 | Medicinal composition for treating cancer |
| EP3206666B1 (en) | 2014-10-16 | 2019-12-11 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
| KR101770605B1 (en) * | 2014-11-17 | 2017-08-23 | 동아에스티 주식회사 | Stable pharmaceutical composition containing Pemetrexed or its pharmaceutically acceptable salt |
| KR101919436B1 (en) * | 2015-05-28 | 2018-11-16 | 주식회사 삼양바이오팜 | Stabilized pharmaceutical composition and preparation method thereof |
| KR101693675B1 (en) | 2015-12-14 | 2017-01-06 | 주식회사 종근당 | Stabilized pharmaceutical composition comprising Pemetrexed or its pharmaceutically acceptable salt |
| US20170239250A1 (en) | 2016-02-19 | 2017-08-24 | Eagle Pharmaceuticals, Inc. | Pemetrexed formulations |
| JP2019094284A (en) * | 2017-11-21 | 2019-06-20 | 日本化薬株式会社 | Injection solution formulation containing pemetrexed |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0162654B1 (en) * | 1989-12-11 | 1998-11-16 | 알렌 제이. 시니스갤리 | N-[pyrrolo (2, 3-d) pyrimidin-3yl acryl]-glutamic acid derivatives |
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2001
- 2001-01-23 PT PT01906523T patent/PT1265612E/en unknown
- 2001-01-23 CN CN01804441A patent/CN1396828A/en active Pending
- 2001-01-23 WO PCT/US2001/000648 patent/WO2001056575A1/en active IP Right Grant
- 2001-01-23 KR KR1020027009930A patent/KR20020081293A/en not_active Application Discontinuation
- 2001-01-23 MX MXPA02007191A patent/MXPA02007191A/en not_active Application Discontinuation
- 2001-01-23 DZ DZ013269A patent/DZ3269A1/en active
- 2001-01-23 NZ NZ519727A patent/NZ519727A/en unknown
- 2001-01-23 PL PL01356705A patent/PL356705A1/en unknown
- 2001-01-23 HU HU0300709A patent/HUP0300709A3/en unknown
- 2001-01-23 DK DK01906523T patent/DK1265612T3/en active
- 2001-01-23 CA CA002399124A patent/CA2399124A1/en not_active Abandoned
- 2001-01-23 CZ CZ20022654A patent/CZ20022654A3/en unknown
- 2001-01-23 DE DE60103512T patent/DE60103512T2/en not_active Expired - Fee Related
- 2001-01-23 AT AT01906523T patent/ATE267601T1/en not_active IP Right Cessation
- 2001-01-23 AU AU34422/01A patent/AU3442201A/en not_active Abandoned
- 2001-01-23 EA EA200200831A patent/EA004708B1/en not_active IP Right Cessation
- 2001-01-23 ES ES01906523T patent/ES2220716T3/en not_active Expired - Lifetime
- 2001-01-23 EP EP01906523A patent/EP1265612B1/en not_active Expired - Lifetime
- 2001-01-23 SK SK1098-2002A patent/SK10982002A3/en unknown
- 2001-01-23 JP JP2001556474A patent/JP2003521518A/en not_active Withdrawn
- 2001-01-23 IL IL15047501A patent/IL150475A0/en unknown
- 2001-01-23 TR TR2004/01436T patent/TR200401436T4/en unknown
- 2001-01-23 BR BR0107958-1A patent/BR0107958A/en not_active IP Right Cessation
- 2001-01-31 MY MYPI20010433A patent/MY129450A/en unknown
- 2001-02-01 CO CO01007346A patent/CO5280222A1/en not_active Application Discontinuation
- 2001-02-01 PE PE2001000116A patent/PE20011223A1/en not_active Application Discontinuation
- 2001-02-02 AR ARP010100507A patent/AR027360A1/en unknown
- 2001-02-02 SV SV2001000301A patent/SV2002000301A/en not_active Application Discontinuation
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2002
- 2002-07-12 NO NO20023379A patent/NO20023379L/en not_active Application Discontinuation
- 2002-07-26 HR HR20020636A patent/HRP20020636A2/en not_active Application Discontinuation
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2003
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